Inflammation reaction is collectively referred to as a defensive reaction of a living body to restore the structure and function of its tissues damaged by infection, trauma and the like. Mobilization of leukocyte cells to the site of inflammation is important for the rapid resolution of the infection and the repair of tissue damages resulting from various traumas. However, erroneous or persistent inflammatory reactions may cause damage and disease to the tissues of the body. For example, inflammatory diseases may result from infections caused by bacteria or viruses such as cerebrospinal meningitis, enteritis, dermatitis, uveitis, encephalitis, adult respiratory distress syndrome, or non-infective factors such as trauma, autoimmune diseases and organ transplant rejection. Inflammatory diseases are classified into acute and chronic inflammatory diseases which have different symptoms and pathological features, respectively. Local symptoms of acute inflammation such as allergies, bacterial and viral infections include changes in blood flow and blood vessel size, changes in vascular permeability and leukocyte infiltration. On the other hand, the main pathological features of chronic inflammation such as rheumatoid arthritis, atherosclerosis, chronic nephritis and liver cirrhosis are that inflammatory factors are not removed and thus monocytes, neutrophils, lymphocytes and plasma cells continuously infiltrate into inflammation sites, resulting in rendering the inflammation reaction chronic.
Inflammatory mediators expressed in inflammatory sites such as cytokines, chemokines, reactive oxygen intermediates, cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and matrix metalloproteinase (MMP) play an important role in the generation and maintenance of inflammatory reactions. Expression of these inflammatory mediators is mediated by transcription factors such as NF-κB (nuclear factor KB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein 1), and HIF-1a (hypoxia-inducible factor 1a).
Sepsis, on the other hand, is a systemic inflammatory reaction caused by an abnormal defense of the body against an infected microorganism. The activation of macrophages is associated with excessive production of inflammatory factors, leading to a severe inflammatory response in the whole body. When there are shown at least two symptoms of a fever with body temperature rising 38° C. or above, hypothermia with body temperature falling to 36° C. or below, a respiratory rate of at least 24 breaths per minute (tachypnea), a pulse rate of at least 90 beats per minute (tachycardia), and a blood test result showing an increase or a marked decrease in leukocyte count, it is called a systemic inflammatory response syndrome (SIRS). it is called sepsis when the systemic inflammatory response syndrome is caused by microbial infection. The sepsis can potentially lead to a septic shock. When sepsis gets worse, the function of various organs (heart, kidney, liver, brain, lungs, etc.) of the body deteriorates. If it gets much worse, it may lead to a shock state. The sepsis may be caused by various types of pathogens. Its highest incidence is induced by bacteria, while being also caused by viruses or fungi. There are pneumonia causing an infection in the lungs, urinary tract infection causing an infection in the bladder and kidneys, cellulitis occurring in skin, appendicitis occurring in the abdomen, or meningitis occurring in the brain, and the like. For example, if a patient with pneumonia has sepsis, his/her brain, heart, liver, lungs, or kidneys can be damaged, while about 20-50% of patients die from septic shock if severe progression occurs. In addition, the sepsis may occur by a post-operative infection. 40 to 90% of patients may die in case a sepsis occurs as a hyperacute inflammatory response due to infection or a postoperative infection.
It is understood that the sepsis occurs as a result of complex interactions between causative organisms and host immune, inflammation and coagulation systems. Both the response of the host and the characteristics of the causative organisms have a significant impact on the prognosis of sepsis. Organ failure observed in sepsis occurs when the host inadequately reacts to causative organisms. If the host's response to the causative organisms is over-amplified, it can lead to organ damage in the host itself. Based on this concept, antagonistic substances against proinflammatory cytokines such as TNF-α, IL-1β and IL-6, which play a leading role in host inflammation, have been applied as a treatment for sepsis, but most of them found unsuccessful. Further, mechanical ventilation, the administration of activated protein C (C), and glucocorticoid treatment have been also tried, but various limitations have been revealed.
Therefore, there is a need for a new therapeutic agent for preventing or treating sepsis and septic shock with a high mortality rate, for which a definite therapeutic agent has yet to be developed.